Wnts are secreted glycoproteins that bind to and activate a receptor complex which includes low-density receptor related protein (LRP5/6) and frizzled proteins. Cadigan, K. M. and Y. I. Liu (2005) Journal of Cell Science 119, 395-402; Nusse, R. (2003) Development 130(22):5297-305.; and Pinson, K. I. (2000) Nature 2000 407(6803):535-8.
It has been disclosed that Wnt/LRP5 regulates bone mass and, that, activation of the Wnt signaling pathway leads to accrual of bone mass. Boyden, L. M. et al. (2002) N Engl J Med 346:1513-1521; Little, R. D. et al. (2002) Am J Hum Genet 70:11-19; and Gong, Y. et al. (2001) Cell 107:513-523. Wnt signaling is tightly regulated by antagonists, which include secreted molecules such as Dickkopf 1 (Dkk-1). Tian, E. et al. (2003) N Engl J Med 349:2483-2494. The high bone mass (HBM) phenotype observed in humans was found to be due to a single point mutation in LRP5 (G171V) that inhibits the ability of Dkk-1 to bind LRP5. Zhang, Y. et al. (2004) Mol Cell Biol. 24(11):4677-84.
The critical role of Wnt signaling in bone formation and bone growth makes Dkk-1 a useful target for the treatment of diseases or conditions where increased osteoblastic activity (increased bone mass density, increased bone formation without a corresponding increase in bone resorption) would be advantageous to the patient, including, for example, by reducing the number of fractures that occur, e.g., as a result of untreated osteoporosis. WO2006/015373 (US2006/0127393) discloses antibodies to Dkk-1 to treat various diseases, including bone disorders. US2008/0193449 discloses antibodies specific for Dkk-1 which inhibit binding of Dkk-1 to LRP5, compositions comprising such antibodies for stimulating bone growth, and compositions comprising such antibodies for treating bone disorders such as osteoporosis.
There remains a need for new bone anabolic agents that antagonize Dkk-1 activity, thereby increasing osteoblastic activity, to treat diseases, conditions and disorders, such as osteoporosis, where such increased bone formation would be advantageous to the patient.